A New 18F-Labeled Myocardial PET Tracer: Myocardial Uptake

A New 18F-Labeled Myocardial PET Tracer:Myocardial Uptake After Permanent and TransientCoronary Occlusion in Rats

Takahiro Higuchi1, Stephan G. Nekolla1, Marc M. Huisman1, Sybille Reder1, Thorsten Poethko1, Ming Yu2,Hans-Jurgen Wester1, David S. Casebier2, Simon P. Robinson2, Rene M. Botnar1, and Markus Schwaiger1

1Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universitat Munchen, Munich, Germany; and 2Departments ofDiscovery Chemistry and Discovery Biology, Bristol-Myers Squibb Medical Imaging, North Billerica, Massachusetts

Conventional myocardial perfusion PET tracers require onsitetracer production because of their short radioactive half-lives.To investigate the potential of a new 18F-labeled pyridazinoneanalog (18F-BMS-747158-02), we characterized this tracer in arat model of permanent and transient coronary occlusion usingsmall-animal PET. Methods: Myocardial 18F-BMS-747158-02distribution in healthy rats (n 5 7), rats with transient (3-min) leftcoronary artery occlusion (n 5 11), and rats with permanent leftcoronary occlusion (n 5 11) was analyzed with a dedicatedsmall-animal PET scanner. Results: Normal hearts demon-strated intense and almost homogeneous tracer uptake through-out the left ventricle for more than 2 h. During permanentcoronary occlusion, PET demonstrated perfusion defects, whichremained unchanged (37.6% 6 8.8%, 37.4% 6 10.2%, and36.2% 6 9.8% left ventricle at 15, 45, and 115 min, respectively,after tracer injection). After transient ischemia, the induced de-fect size decreased significantly after reperfusion (16.2% 6

9.3%, 6.0% 6 6.5%, and 1.4% 6 1.3% left ventricle). Tracerreinjection after transient ischemia resulted in normalization ofthe induced defect. Conclusion: Coronary occlusion yieldeddistinct myocardial 18F-BMS-747158-02 uptake defects in thearea of ischemia, which demonstrated normalization of activityafter reperfusion and reinjection. These promising kinetic param-eters may allow for assessment of flow using exercise–rest pro-tocols similar to those used in combination with exercise and restperfusion SPECT.

Key Words: cardiology (clinical); PET; animal imaging; 18F; in-farction; ischemia; perfusion

J Nucl Med 2008; 49:1715–1722DOI: 10.2967/jnumed.108.053967

Myocardial exercise–rest perfusion imaging usingSPECT with 201Tl, 99mTc-sestamibi, or 99mTc-tetrofosmineis widely applied for clinically diagnosing and determining

the prognosis of ischemic heart disease (1). However, false-positive findings caused by attenuation artifacts and un-derestimation of absolute perfusion abnormalities in patientswith balanced 3-vessel disease are well-known limitations ofthe method (2). Moreover, the recent development of angio-genic therapies may require high-sensitivity, high-resolutionimaging for monitoring changes in perfusion more subtlethan those that occur with conventional therapies (3).

PET can overcome some limitations of SPECT by pro-viding better temporal and spatial resolution, greater sensi-tivity, and established algorithms for attenuation correction(4,5). There are 3 well-established tracers for myocardialPET perfusion imaging: 82Rb, 13N-ammonia, and 15O-water.These tracers have short radioactive half-lives of 76 s, 10 min,and 2.1 min, respectively. 82Rb is produced by a radionuclidegenerator system, whereas production of 13N-ammonia and15O-water require an expensive on-site cyclotron. In addi-tion, the short radioactive half-life requires imaging proto-cols with tracer injections while the patient is on the scanner.These temporal limitations make it difficult to perform theexercise stress examinations commonly used in SPECTmyocardial perfusion imaging.

18F-labeled perfusion PET tracers, including 18F-BMS-747158-02, for the evaluation of myocardial perfusion haverecently been introduced (6–10). 18F-labeled tracers withradioactive half-lives of 110 min overcome the half-lifelimitations of previously used PET perfusion tracers. Suchtracers may be distributed by a central cyclotron facility ina manner similar to 18F-FDG. Moreover, 18F provides betterimage quality and spatial resolution because it emits alower-energy positron that travels a shorter distance intissue before annihilation (11,12). Initial reports of 18F-BMS-747158-02 showed the compound to have promisingproperties as a new myocardial perfusion tracer, such as aspecific, high myocardial extraction fraction and retentionat different flow rates in rat and rabbit models (8–10).However, whether the kinetics of 18F-BMS-747158-02 innormally perfused and transiently ischemic myocardiumreflect suitability for clinical stress perfusion studies re-mains unknown. In this study, we aimed to further explore

Received Apr. 29, 2008; revision accepted Jun. 24, 2008.For correspondence or reprints contact: Takahiro Higuchi, Nuklearmedizinische

Klinik der Technischen Universitat Munchen, Ismaninger Strasse 22, 81675Munich, Germany.

E-mail: [email protected] ª 2008 by the Society of Nuclear Medicine, Inc.

18F-LABELED MYOCARDIAL PET TRACER • Higuchi et al. 1715

by on April 4, 2018. For personal use only. jnm.snmjournals.org Downloaded from

http://jnm.snmjournals.org/

the potential clinical application of the novel PET tracer18F-BMS-747158-02 for the diagnosis of coronary arterydisease using permanent and transient coronary occlusionin rats and imaging with small-animal PET.

MATERIALS AND METHODS

18F-BMS-747158-02 was characterized using a small-animal PETsystem and rat models. 18F-BMS-747158-02 uptake in the myocar-dium of healthy rats was assessed. For comparison, 13N-ammoniauptake in other healthy rats was studied. Furthermore, myocardial18F-BMS-747158-02 uptake and time-dependent changes in tracerdistribution were assessed in rats with permanent or transientcoronary occlusion. One rat was studied with 13N-ammonia PETand 18F-BMS-747158-02 PET 1 wk after permanent coronary arteryocclusion.

Experimental protocols were approved by the regional govern-mental commission of animal protection (Regierung von Ober-bayern, Germany) and conformed with the guidelines of the U.S.National Institutes of Health (13).

Tracer ProductionTracer production was performed as described elsewhere (8–10).

Animal PreparationMale Wistar rats weighing 250–300 g were used in all exper-

iments. Healthy rats (n 5 7), rats with permanent left coronaryartery (LCA) occlusion (n 5 11), and rats with transient LCAocclusion (n 5 11) were studied (Fig. 1). Before the intervention,the rats were anesthetized with intramuscularly administeredmidazolam (0.1 mg/kg), fentanyl (1 mg/kg), and medetomidine(10 mg/kg). The rats were mechanically ventilated and underwentthoracotomy.

In rats with permanent LCA occlusion, a 7–0 polypropylenesuture on a small, curved needle was passed through the myocar-dium beneath the LCA and ligated to occlude the LCA (14).Coronary occlusion was confirmed by the regional cyanosis of themyocardial surface.

In the animals with transient LCA occlusion, the suture waspassed through the myocardium beneath the LCA. Subsequently,both suture ends were passed through a small vinyl tube to make asnare. The suture material was pulled tightly against the vinyl tubeto occlude the LCA. After a 3-min occlusion, reperfusion wasobtained by release of the snare and confirmed by a myocardialblush over the area at risk (15). After the surgery, the chest wasclosed, and the rats were moved to the PET scanner.

18F-BMS-747158-02 PET ProtocolsFive series of experiments (protocols A–E) were performed

(Fig. 1).Protocol A was designed to address the myocardial distribution

of 18F-BMS-747158-02 in normal rats over 120 min after tracerinjection (n 5 5). Thirty-seven megabecquerels of 18F-BMS-747158-02 were injected into the tail vein just before the start ofPET data acquisition.

Protocol B evaluated the effect of coronary occlusion. The ratswere injected with 18F-BMS-747158-02 (37 MBq) 1 min afterpermanent occlusion of the LCA and imaged from 10 to 120 minafter tracer injection (n 5 5).

Protocol C was designed to analyze the tracer redistribution in areperfusion model. The LCA was occluded for a period of 3 min,and 37 MBq of 118F-BMS-747158-02 were injected 1 min after

occlusion of the LCA. Image acquisition continued from 10 to 120min after tracer injection (n 5 5).

Protocols D and E were designed to investigate the effects oftracer reinjection on the cardiac tracer distribution in permanent(D) (n 5 6) or transient (E) (n 5 6) coronary occlusion. In bothprotocols, 18F-BMS-747158-02 was injected as described in pro-tocols B and C at 10 min before the start of image acquisition (17MBq) and 30 min after the start of image acquisition (37 MBq),which continued for 60 min.

13N-Ammonia PET of Healthy Rats and CoronaryOcclusion Model

13N-ammonia PET was performed on 8 healthy rats. 13N-ammonia (55 MBq) was injected, and data were acquired from5 to 15 min after tracer injection.

One rat was imaged 1 wk after permanent occlusion of the LCAwith both 13N-ammonia and 18F-BMS-747158-02 PET. Imagingwas performed for 10 min after a 5-min delay after injection of 55MBq of 13N-ammonia. After a delay of 40 min to allow forradioactive decay, 37 MBq of 18F-BMS-747158-02 were admin-istered, and a 10-min PET acquisition was performed.

PET Acquisition and ReconstructionAll PET was performed with the animals prone. A dedicated

small-animal PET scanner was used (microPET Focus 120;

FIGURE 1. Schemas of experimental protocols of permanentand transient coronary occlusion and imaging: normal heart (A),permanent LCA occlusion (B), transient LCA occlusion (C), re-injection after permanent LCA occlusion (D), and reinjection aftertransient LCA occlusion (E). 18F-BMS 5 18F-BMS-747158-02.

1716 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 10 • October 2008



Siemens Medical Solutions). Data were acquired in list-modeformat and reconstructed into a dynamic image with 10-minframes for 18F-BMS-747158-02 PET and a single frame for 13N-ammonia PET.

The reconstruction was done using filtered backprojection witha cutoff at the Nyquist frequency, and the resulting images had128 · 128 · 95 voxels with a voxel size of 0.43 · 0.43 · 0.80 mm.Data were normalized and corrected for randoms, dead time, anddecay.

Data AnalysisThe PET images were analyzed with the ASIPro software

package (Siemens Medical Solutions) and the Munich Heartsoftware package (14,16).

Regions of interests were manually defined in a mid coronalslice at the heart (anterior wall) and in the blood pool (leftventricle), lung (right), and liver using ASIPro software. Percent-ages of injected dose/cm3 of tissue in the heart region of interestand the ratio of tracer activity between the heart and other organswere calculated.

Volumetric sampling was applied to delineate 3-dimensionaltracer distributions throughout the left ventricular myocardium,

and tracer concentrations at each sampling point were displayed ina polar map using Munich Heart software (14,16). Mean percent-age uptake (expressed as a percentage of maximal uptake) wascalculated for 5 segments in normal rat hearts. Tracer-uptakedefects were characterized as having less than 50% activity whencompared with the point of maximum activity in the myocardium.The mean percentage uptakes and regional defects were evaluatedat 15, 45, and 115 min after tracer injection.

Statistical AnalysisAll results were expressed as mean 6 SD. Statistical analysis

was done with StatMate III (ATMS Co., Ltd.). Uptake ratio wascompared between 2 groups by means of the Mann–Whitney test.Differences between group comparisons were identified usingANOVA followed by the Scheffe multiple-contrast hypothesis test.A value of P less than 0.05 was considered statistically significant.

RESULTS

18F-BMS-747158-02 Distribution in Normal Rat Hearts

Figure 2 demonstrates in vivo analysis of 18F-BMS-747158-02 uptake in healthy rats. The left ventricular myo-

FIGURE 2. (A) Examples of 18F-BMS-747158-02 (18F-BMS) PET images of chest of healthy rat at 15, 45, and 115 min after tracerinjection and 13N-ammonia PET image at 10 min in coronal view. Example of regions of interest for measurement of tracer activity isdisplayed in white box. (B and C) Ratio of 18F-BMS uptake between myocardium and surrounding organs (B) and absolute 18F-BMS activity of myocardium (%ID/cm3) (C). (D) Comparison of 18F-BMS uptake ratios at 15 min after injection and 13N-ammonia at10 min.




cardium showed excellent contrast to surrounding tissues inall rats. High tracer accumulation was preserved in themyocardium throughout the imaging period of 2 h (percent-age injected dose [%ID]/cm3 . 2.0 from 15 to 115 min), witha slight decrease from 30 min (Fig. 2C). The half-life ofmyocardial tracer activity on PET images was calculated as265 min using linear fitting of the time–activity curve from 25to 115 min (y 5 20.0048x 1 2.53, r 5 0.965; y 5 traceractivity [%ID/cm3], x 5 time after tracer injection [min]).Time-dependent changes in tracer distribution in the heartand other organs were observed. Heart-to-lung ratio andheart–to–left ventricle blood-pool ratio decreased over time(heart-to-lung ratio from 14.6 6 3.10 at 15 min to 8.70 6 2.4at 115 min; heart–to–left ventricle blood pool ratio from3.47 6 0.76 at 15 min to 2.83 6 0.54 at 115 min) and heart-to-liver ratio increased (from 2.07 6 0.80 at 15 min to 2.82 6

0.39 at 115 min) (Figs. 2A and 2B). These ratios, whencompared with 13N-ammonia (heart-to-lung, 3.60 6 0.80;heart-to-liver, 1.05 6 0.49; heart–to–left ventricle blood pool,2.08 6 0.16), show significantly improved myocardium-to-tissue contrast (Figs. 2A and 2D).

18F-BMS-747158-02 uptake in the myocardium was al-most homogeneous throughout the left ventricle. However,small differences were observed, with the lowest uptake in

apical segments, when compared with anterior, septal, infe-rior, and lateral areas at 15, 45, and 115 min after tracerinjection. Small (approximately 5%) but significant differ-ences in tracer distribution were found in the lateral wallat 115 min, as compared with 15 and 45 min (Fig. 3).

18F-BMS-747158-02 Uptake in LCA Occlusion18F-BMS-747158-02 PET images demonstrated a defect

in the myocardium of all rats with LCA occlusion at 15 minafter tracer injection. As shown in Figure 4, the induced18F-BMS-747158-02 uptake defect visualized at 15 mincorresponded precisely to the defect in 13N-ammonia im-ages. Images obtained using 18F-BMS-747158-02 demon-strated improved contrast and higher resolution resulting inbetter delineation of induced lesions, despite a higherinjected dose of 13N-ammonia (57 MBq) versus 18F-BMS-747158-02 (37 MBq).

18F-BMS-747158-02 Redistribution After Reperfusion

The defect size induced by permanent LCA occlusiondid not change over 2 h (37.6% 6 8.8% left ventricle at 15min, 37.4% 6 10.2% left ventricle at 45 min, and 36.2% 6

9.8% left ventricle at 115 min). The tracer activity (%ID/cm3) in normal myocardium and the induced defect werealso constant throughout the imaging period. In contrast,

FIGURE 3. Normal pattern of left ven-tricular 18F-BMS-747158-02 (18F-BMS)distribution at 15, 45, and 115 min aftertracer injection as shown in mean polarmaps (A) and as mean uptake values (%left ventricle maximum) with SD (B).Uptake was nearly homogeneousthroughout left ventricle, with slightlylower uptake in apical segment.

FIGURE 4. Short-axis images of ratheart 1 wk after coronary occlusion using18F-BMS-747158-02 (18F-BMS) PET and13N-ammonia PET. Arrows indicate lo-calization of myocardial infarction.




tracer redistributed in the induced defect after reperfusionafter 3 min of coronary occlusion (Fig. 5). A significantreduction (P , 0.01) in perfusion defect size occurred af-ter reperfusion (16.2% 6 9.3% left ventricle at 15 min,6.0% 6 6.5% left ventricle at 45 min, and 1.4% 6 1.3%left ventricle at 115 min). Tracer activity in the defectincreased over time after reperfusion, whereas the activityof normally perfused myocardium remained constant. Inrats with transient LCA occlusion (3 min) and reperfusion,the activity within the defect approached normal myocar-dial activity at 115 min after tracer injection (Fig. 6).

Tracer reinjection did not change the defect size (29.7% 6

10.8% at 15 min, 30.5% 6 10.8% after reinjection) inanimals with permanent LCA occlusion. In contrast, ratswith transient LCA occlusion demonstrated resolution ofthe induced defect, with increased tracer activity afterreinjection (defect size: 15.0% 6 5.5% at 15 min, 0% 6

0% after reinjection) (Fig. 7). The defect took 2 h todisappear without reinjection (protocol C), but tracerreinjection enhanced the normalization process, whichbecame apparent rapidly after reinjection in the transientLCA occlusion model (protocol E).

DISCUSSION

The results of this study indicate promising properties for18F-BMS-747158-02 as a novel 18F-labeled PET tracer forthe diagnosis and evaluation of coronary artery disease. Inthe normal rat heart, tracer uptake in the left ventricularwall shows high contrast to surrounding tissue and highmyocardial retention throughout the imaging period of 2 h.This finding confirms the previously reported high first-passextraction and high myocardial retention in isolated per-fused rat hearts (10). The high contrast ratio betweenmyocardial and hepatic tissue represents a favorable featurefor the evaluation of the inferior wall of the left ventricle, ascompared with 13N-ammonia. In animals with coronaryocclusion, the induced defect was clearly delineated and

remained unchanged over the entire imaging protocol. Incontrast, reperfusion after short, transient ischemia (3 min)yielded tracer redistribution to the induced defect. Tracerreinjection further enhanced the normalization process. Theclinical application of this tracer for the diagnosis ofcoronary artery disease and for the assessment of tissueviability may involve tracer injection under physical stressconditions with early and late imaging studies.

PET has been proven to be a reliable and efficienttechnique to assess myocardial perfusion in patients withknown or suspected coronary artery disease (17,18). Re-cently, Bateman et al. compared the diagnostic accuracy ofrest/pharmacologic stress perfusion with 99mTc-sestamibiSPECT and 82Rb PET in matched patient populations (5).The results demonstrated higher overall accuracy for PET(89%) than for SPECT (79%), based on an angiographiccriterion of more than 70% coronary stenosis. In patientswith multivessel coronary disease, PET identified moredefects than did SPECT (71% vs. 48%).

Conventional PET perfusion tracers such as 3N-ammonia,15O-water, or 82Rb have short physical half-lives, whichallow repeated studies after decay. A pharmacologic stressprotocol is commonly used for conventional PET perfusionstudies because of technical limitations in performing exer-cise stress testing with short-lived isotopes. On the otherhand, exercise stress testing is often preferred for SPECTperfusion imaging because it offers important clinical andhemodynamic information in addition to myocardial perfu-sion. Recently, Chow et al. compared treadmill exercise anddipyridamole stress using 13N-ammonia perfusion PET (19).They found larger and more severe perfusion defects withphysical exercise than with dipyridamole, indicating thatexercise may offer diagnostic advantages for 13N-ammoniaperfusion imaging. Because of the longer half-life of 18F,18F-labeled perfusion tracers can potentially be used inexercise stress testing by injection of tracer during peakexercise and postinjection imaging. However, the longerhalf-life also limits the use of tracer in protocols involvingrepeated measurements on a single day. Therefore, protocolsinvolving stress and rest studies on separate days, orvalidation of a tracer reinjection protocol, are required. Inaddition, an increased radiation dose should be consideredwhen determining the injection dose of the tracer.

The chemical structure of BMS-747158-02, a modifica-tion of the pyridazinone insecticide pyidaben, was de-scribed in previous publications (8–10). These compoundsare known to bind tightly to mitochondrial complex I, withhigh affinity in myocardial tissue (8,9,20). Observed highlyselective myocardial tracer uptake may be explained partlyby the high content of mitochondria in the left ventricularmyocardium. Given the high extraction fraction, whichappeared to be flow-independent as measured in isolated rathearts (10), 18F-BMS-747158-02 uptake is most likely toreflect blood flow. The feasibility of quantification requiresconfirmation in large-animal models using microspherereference measurements. In addition, the influence of hy-

FIGURE 5. Representative short-axis images of rat heartswithout coronary occlusion, permanent coronary occlusion, andtransient coronary occlusion at different time points after traceradministration. Tracer redistribution is seen in induced defectafter reperfusion (arrows).




poxia on tracer retention, which may cause changes inmitochondrial structure and function, have not been ad-dressed. Similar observations have been reported for 99mTc-sestamibi but have not affected its clinical application(21,22).

Redistribution is an advantage of 201Tl SPECT tracerkinetics that is not shared by 99mTc perfusion SPECTtracers for the assessment of myocardial viability usingstress/rest redistribution protocols. Experimental studiesafter coronary occlusion and reperfusion in dogs showed

FIGURE 6. Changes in myocardial 18F-BMS-747158-02 (18F-BMS) distribution after both permanent and transient coronaryocclusion are shown in representative polar maps (A) and as defect area expressed as percentage of total left ventricularmyocardium (B). Normalized counts of circumferential profiles after permanent occlusion (C) or transient occlusion (D) are alsoshown. Mean values are shown for tracer activity in induced defect and normally perfused myocardium after permanent (E) andtransient occlusion (F). Tracer activity in defect increased over time after reperfusion in transient coronary occlusion.




in the induced defect an increase in relative 201Tl activity(23) caused by the differential washout rates in normal andpostischemic myocardium. Faster 201Tl washout in normalmyocardium results in a decrease in defect size based onthe evaluation of relative myocardial tracer distributions.

We observed tracer redistribution with 18F-BMS-747158-02 after reperfusion. In contrast to 201Tl kinetics,we found time-dependent increases in tracer activity in theinduced defect whereas the activity remained constant innormally perfused myocardium. High extraction fractionand minimal washout of the tracer from myocardium weredemonstrated in isolated perfused rat heart (10). Therefore,after initial tracer uptake, tracer washout from extracardiacorgans, as well as some recirculation within the myocar-dium, may be possible sources of the increased activity.Although the mechanism of redistribution may differ fromthat of 201Tl redistribution, the observed kinetics may allowfor a clinical protocol in the diagnosis of coronary arterydisease similar to conventional stress/rest 201Tl perfusionimaging. However, the kinetics observed in rat heart maynot directly apply to other species, including humans.Future studies on other species are required to confirmthe redistribution and to define the optimal time windowbetween tracer injection and imaging to maintain a highsensitivity for detection of perfusion abnormalities.

CONCLUSION

We found that cardiac accumulation of 18F-BMS-747158-02 in normal rat hearts was rapid, relatively ho-mogeneous, high, and persisted over 2 h. Additionally,transient coronary occlusion demonstrated well-delineateddefects in tracer uptake followed by tracer redistributionafter reperfusion. These results indicate that this 18F-labeled compound may be an excellent candidate in theassessment of myocardial perfusion using PET and con-ventional physical exercise stress protocols, which arecurrently used in tandem with SPECT.

ACKNOWLEDGMENTS

We are grateful to Antti Sarastie and Som Javadi for theircareful editorial assistance. This study was supported by a

research grant from Bristol-Myers Squibb Medical Imag-ing. Ming Yu, David S. Casebier, and Simon P. Robinsonare employees of Bristol-Myers Squibb Medical Imaging.

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Doi: 10.2967/jnumed.108.053967Published online: September 15, 2008.

2008;49:1715-1722.J Nucl Med. Wester, David S. Casebier, Simon P. Robinson, Rene M. Botnar and Markus SchwaigerTakahiro Higuchi, Stephan G. Nekolla, Marc M. Huisman, Sybille Reder, Thorsten Poethko, Ming Yu, Hans-Jurgen Transient Coronary Occlusion in Rats

F-Labeled Myocardial PET Tracer: Myocardial Uptake After Permanent and18A New

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A New 18F-Labeled Myocardial PET Tracer: Myocardial Uptake